rs76304838

chr2-227261062-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000091.5(COL4A3):c.1115-20T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00638 in 1,603,440 control chromosomes in the GnomAD database, including 559 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (286 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (273 hom.)
• Consequence: COL4A3 NM_000091.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.111

Genes affected

COL4A3 (HGNC:2204): (collagen type IV alpha 3 chain) Type IV collagen, the major structural component of basement membranes, is a multimeric protein composed of 3 alpha subunits. These subunits are encoded by 6 different genes, alpha 1 through alpha 6, each of which can form a triple helix structure with 2 other subunits to form type IV collagen. This gene encodes alpha 3. In the Goodpasture syndrome, autoantibodies bind to the collagen molecules in the basement membranes of alveoli and glomeruli. The epitopes that elicit these autoantibodies are localized largely to the non-collagenous C-terminal domain of the protein. A specific kinase phosphorylates amino acids in this same C-terminal region and the expression of this kinase is upregulated during pathogenesis. This gene is also linked to an autosomal recessive form of Alport syndrome. The mutations contributing to this syndrome are also located within the exons that encode this C-terminal region. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. [provided by RefSeq, Jun 2010]

MFF-DT (HGNC:41067): (MFF divergent transcript)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 2-227261062-T-C is Benign according to our data. Variant chr2-227261062-T-C is described in ClinVar as [Benign]. Clinvar id is 254975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227261062-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A3	NM_000091.5	c.1115-20T>C		intron_variant		ENST00000396578.8
MFF-DT	NR_102371.1	n.1487-1779A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A3	ENST00000396578.8	c.1115-20T>C		intron_variant		1	NM_000091.5	P1
MFF-DT	ENST00000439598.6	n.1487-1779A>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0342 AC: 5208 AN: 152210 Hom.: 285 Cov.: 33

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.0225

GnomAD3 exomes AF: 0.00865 AC: 2155 AN: 249242 Hom.: 131 AF XY: 0.00646 AC XY: 874 AN XY: 135232

Gnomad AFR exome AF: 0.122

Gnomad AMR exome AF: 0.00516

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000522

Gnomad OTH exome AF: 0.00315

GnomAD4 exome AF: 0.00345 AC: 5007 AN: 1451112 Hom.: 273 Cov.: 28 AF XY: 0.00298 AC XY: 2153 AN XY: 722760

Gnomad4 AFR exome AF: 0.123

Gnomad4 AMR exome AF: 0.00590

Gnomad4 ASJ exome AF: 0.000192

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000199

Gnomad4 OTH exome AF: 0.00698

GnomAD4 genome AF: 0.0343 AC: 5219 AN: 152328 Hom.: 286 Cov.: 33 AF XY: 0.0329 AC XY: 2450 AN XY: 74494

Gnomad4 AFR AF: 0.119

Gnomad4 AMR AF: 0.0114

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.0222

Alfa AF: 0.0167 Hom.: 18

Bravo AF: 0.0383

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	8.8
Dann	Benign	0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs76304838; hg19: chr2-228125778;